Clinical outcome of single agent volasertib (BI 6727) as second-line treatment of patients (pts) with advanced or metastatic urothelial cancer (UC).

Stadler, Walter M.; Vaughn, David J.; Sonpavde, Guru; Vogelzang, N. J.; Tagawa, S.T.; Petrylak, Daniel P.; Rosen, Peter J.; Lin, Chun‐Ying; Mahoney, John F.; Modi, Sanjiv; Lee, P.; Ernstoff, Marc S.; Su, W.; Spira, Alexander I.; Kaci, M. Ould; Taube, Tillmann; Vinisko, Richard; Schloss, Charles; Zhao, Carol; Carducci, Michael A.

doi:10.1200/jco.2011.29.15_suppl.4567

Cited by 5 publications

(9 citation statements)

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“…The Plk1 inhibitor volasertib (BI 6727) has moved to phase II in order to determine its antitumor activity and safety profile. Preliminary results from a clinical trial with volasertib as single-agent showed encouraging antitumor activity, with nonhematologic adverse events that were mild and uncommon [11]. We show that colon cancer-initiating cells (CCIC) are actively proliferating both in vitro and in vivo, overexpress Plk1, and are sensitive to Plk1 inhibitors.…”

Section: Introductionmentioning

confidence: 88%

Proliferation State and Polo-Like Kinase1 Dependence of Tumorigenic Colon Cancer Cells

et al. 2012

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Tumor-initiating cells are responsible for tumor maintenance and relapse in solid and hematologic cancers. Although tumor-initiating cells were initially believed to be mainly quiescent, rapidly proliferating tumorigenic cells were found in breast cancer. In colon cancer, the proliferative activity of the tumorigenic population has not been defined, although it represents an essential parameter for the development of more effective therapeutic strategies. Here, we show that tumorigenic colon cancer cells can be found in a rapidly proliferating state in vitro and in vivo, both in human tumors and mouse xenografts. Inhibitors of polo-like kinase1 (Plk1), a mitotic kinase essential for cell proliferation, demonstrated maximal efficiency over other targeted compounds and chemotherapeutic agents in inducing death of colon cancer-initiating cells in vitro. In vivo, Plk1 inhibitors killed CD1331 colon cancer cells leading to complete growth arrest of colon cancer stem cell-derived xenografts, whereas chemotherapeutic agents only slowed tumor progression. While chemotherapy treatment increased CD133

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Section: Introductionmentioning

confidence: 88%

Proliferation State and Polo-Like Kinase1 Dependence of Tumorigenic Colon Cancer Cells

et al. 2012

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“…Individual patient data were obtained from 748 patients enrolled in 12 phase 2 trials (nine nonrandomized, three randomized) of second-line therapy for progressive, advanced UC, which were either published or presented at major conferences (Table 1) [3–9,12,15,16]. Prior chemotherapy was administered in the perioperative and/or metastatic disease settings.…”

Section: Methodsmentioning

confidence: 99%

Time from Prior Chemotherapy Enhances Prognostic Risk Grouping in the Second-line Setting of Advanced Urothelial Carcinoma: A Retrospective Analysis of Pooled, Prospective Phase 2 Trials

et al. 2013

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Background Outcomes for patients in the second-line setting of advanced urothelial carcinoma (UC) are dismal. The recognized prognostic factors in this context are Eastern Cooperative Oncology Group (ECOG) performance status (PS) >0, hemoglobin level (Hb) <10 g/dl, and liver metastasis (LM). Objectives The purpose of this retrospective study of prospective trials was to investigate the prognostic value of time from prior chemotherapy (TFPC) independent of known prognostic factors. Design, setting, and participants: Data from patients from seven prospective trials with available baseline TFPC, Hb, PS, and LM values were used for retrospective analysis (n = 570). External validation was conducted in a second-line phase 3 trial comparing best supportive care (BSC) versus vinflunine plus BSC (n = 352). Outcome measurements and statistical analysis Cox proportional hazards regression was used to evaluate the association of factors, with overall survival (OS) and progression-free survival (PFS) being the respective primary and secondary outcome measures. Results and limitations ECOG-PS >0, LM, Hb <10 g/dl, and shorter TFPC were significant prognostic factors for OS and PFS on multivariable analysis. Patients with zero, one, two, and three to four factors demonstrated median OS of 12.2, 6.7, 5.1, and 3.0 mo, respectively (concordance statistic = 0.638). Setting of prior chemotherapy (metastatic disease vs perioperative) and prior platinum agent (cisplatin or carboplatin) were not prognostic factors. External validation demonstrated a significant association of TFPC with PFS on univariable and most multivariable analyses, and with OS on univariable analyses. Limitations of retrospective analyses are applicable. Conclusions Shorter TFPC enhances prognostic classification independent of ECOG-PS>0, Hb<10 g/ dl, and LM in the setting of second-line therapy for advanced UC. These data may facilitate drug development and interpretation of trials.

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“…Individual patient data were obtained from 748 patients enrolled in 12 available phase II trials (nine non‐randomized, three randomized) of second‐line therapy for advanced UC (Table ). These trials enrolled patients who had received previous therapy in the peri‐operative or metastatic disease settings.…”

Section: Methodsmentioning

confidence: 99%

“…*Trials that did not have TFPC data were completely excluded [6,12,16]. † Patients with unavailable Hb, LM or ECOG‐PS were excluded [2,3,5,9,17].…”

Section: Methodsmentioning

confidence: 99%

A nomogram including baseline prognostic factors to estimate the activity of second‐line therapy for advanced urothelial carcinoma

Pond

Agarwal

Bellmunt³

et al. 2014

BJU International

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ObjectiveTo study the impact of the prognostic factors liver metastasis (LM), anaemia (haemoglobin [Hb] <10 g/dL), Eastern Cooperative Oncology Group performance status (ECOG-PS) ≥1 and time from previous chemotherapy (TFPC) on the activity of second-line therapy for advanced urothelial carcinoma (UC). Patients and MethodsTwelve phase II trials evaluating second-line chemotherapy and/or biological characteristics (n = 748) in patients with progressive disease were pooled.Progression-free survival (PFS) was defined as tumour progression or death from any cause.The PFS rate at 6 months (PFS6) was defined from the date of registration and calculated using the Kaplan-Meier method.Response rate (RR) was defined using Response Evaluation Criteria in Solid Tumours (RECIST) 1.0.A nomogram predicting PFS6 was constructed using the RMS software package in R (http://www.r-project.org). ResultsData regarding progression, anaemia, LM, ECOG-PS and TFPC were available from 570 patients in nine phase II trials.The overall median PFS was 2.7 months, PFS6 was 22.2% (95% confidence interval 18.8-25.9) and the RR was 17.5% (95% CI: 14.5-20.9%).For every unit increase in risk group, the hazard of progression in 6 months increased by 41% and the odds of response decreased by 48%.A nomogram was constructed to predict PFS6 on an individual patient level.The model was internally validated and was shown to have acceptable calibration performance. ConclusionsThe RR and PFS6 vary as a function of baseline prognostic factors in patients receiving second-line therapy for advanced UC.

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Clinical outcome of single agent volasertib (BI 6727) as second-line treatment of patients (pts) with advanced or metastatic urothelial cancer (UC).

Cited by 5 publications

References 0 publications

Proliferation State and Polo-Like Kinase1 Dependence of Tumorigenic Colon Cancer Cells

Proliferation State and Polo-Like Kinase1 Dependence of Tumorigenic Colon Cancer Cells

Time from Prior Chemotherapy Enhances Prognostic Risk Grouping in the Second-line Setting of Advanced Urothelial Carcinoma: A Retrospective Analysis of Pooled, Prospective Phase 2 Trials

A nomogram including baseline prognostic factors to estimate the activity of second‐line therapy for advanced urothelial carcinoma

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